Defining the role of GLP-1 in the enteroinsulinar axis in type 2 diabetes using DPP-4 inhibition and GLP-1 receptor blockade

TY - JOUR

T1 - Defining the role of GLP-1 in the enteroinsulinar axis in type 2 diabetes using DPP-4 inhibition and GLP-1 receptor blockade

AU - Aulinger, Benedikt A

AU - Bedorf, Anne

AU - Kutscherauer, Gabriele

AU - de Heer, Jocelyn

AU - Holst, Jens Juul

AU - Göke, Burkhard

AU - Schirra, Jörg

PY - 2014/3

Y1 - 2014/3

N2 - Understanding the incretin pathway has led to significant advancements in the treatment of type 2 diabetes (T2D). Still, the exact mechanisms are not fully understood. In a randomized, placebo-controlled, four-period, crossover study in 24 patients with T2D, dipeptidyl peptidase-4 (DPP-4) inhibition and its glucose-lowering actions were tested after an oral glucose tolerance test (OGTT). The contribution of GLP-1 was examined by infusion of the GLP-1 receptor (GLP-1r) antagonist exendin-9. DPP-4 inhibition reduced glycemia and enhanced insulin levels and the incretin effect (IE). Glucagon was suppressed, and gastric emptying (GE) was decelerated. Exendin-9 increased glucose levels and glucagon secretion, attenuated insulinemia and the IE, and accelerated GE. With the GLP-1r antagonist, the glucose-lowering effects of DPP-4 inhibition were reduced by ∼ 50%. However, a significant effect on insulin secretion remained during GLP-1r blockade, whereas the inhibitory effects of DPP-4 inhibition on glucagon and GE were abolished. Thus, in this cohort of T2D patients with a substantial IE, GLP-1 contributed ∼ 50% to the insulin excursion after an OGTT with and without DPP-4 inhibition. Thus, a significant DPP-4-sensitive glucose-lowering mechanism contributes to glycemic control in T2D patients that may be not mediated by circulating GLP-1.

AB - Understanding the incretin pathway has led to significant advancements in the treatment of type 2 diabetes (T2D). Still, the exact mechanisms are not fully understood. In a randomized, placebo-controlled, four-period, crossover study in 24 patients with T2D, dipeptidyl peptidase-4 (DPP-4) inhibition and its glucose-lowering actions were tested after an oral glucose tolerance test (OGTT). The contribution of GLP-1 was examined by infusion of the GLP-1 receptor (GLP-1r) antagonist exendin-9. DPP-4 inhibition reduced glycemia and enhanced insulin levels and the incretin effect (IE). Glucagon was suppressed, and gastric emptying (GE) was decelerated. Exendin-9 increased glucose levels and glucagon secretion, attenuated insulinemia and the IE, and accelerated GE. With the GLP-1r antagonist, the glucose-lowering effects of DPP-4 inhibition were reduced by ∼ 50%. However, a significant effect on insulin secretion remained during GLP-1r blockade, whereas the inhibitory effects of DPP-4 inhibition on glucagon and GE were abolished. Thus, in this cohort of T2D patients with a substantial IE, GLP-1 contributed ∼ 50% to the insulin excursion after an OGTT with and without DPP-4 inhibition. Thus, a significant DPP-4-sensitive glucose-lowering mechanism contributes to glycemic control in T2D patients that may be not mediated by circulating GLP-1.

KW - Blood Glucose

KW - C-Peptide

KW - Cross-Over Studies

KW - Diabetes Mellitus, Type 2

KW - Dipeptidyl-Peptidase IV Inhibitors

KW - Fasting

KW - Female

KW - Gastric Emptying

KW - Glucagon-Like Peptide 1

KW - Glucose Tolerance Test

KW - Humans

KW - Incretins

KW - Insulin

KW - Male

KW - Middle Aged

KW - Pyrazines

KW - Receptors, Glucagon

KW - Triazoles

U2 - 10.2337/db13-1455

DO - 10.2337/db13-1455

M3 - Journal article

C2 - 24296715

SN - 0012-1797

VL - 63

SP - 1079

EP - 1092

JO - Diabetes

JF - Diabetes

IS - 3

ER -